This invention relates to microspheres. More particularly it relates to processes for the preparation of microspheres of a polymer and a core material and to products produced thereby. In one particular aspect it relates to processes for the preparation of microspheres of a polymer and a drug and to products produced thereby.
In another aspect it relates to processes for modifying the release rate of a core material by the use of an alkaline agent during the preparation of the microspheres.
Broadly, the microspheres of this invention may be described as: microcapsules of a core material, e.g., drug, and a polymer wherein the polymer coats a drug particle; or microprills which are homogeneous mixtures of a core material, e.g., drug and a polymer. The processes of this invention are directed to the modification of the release rate of a core material from microspheres by the novel use of an alkaline agent during the preparation of the microspheres.
Microencapsulation processes based on solvent removal from emulsions are known in the prior art and have been reviewed in various publications. These include: M. Morishita et al. in "Microencapsulation: Processes and Applications," edited by J. E. Vandegaer, Plenum Press, NY, 1974, pp. 115-116; A. Watanabe and T. Hayashi in "Microencapsulation," edited by M. R. Nixon, Marcel Dekker, Inc., NY, 1976, pp. 18-19; A. Kondo, "Microcapsule Processing and Technology," edited and revised by J. W. Van Valkenburg from the original 1970 Japanese edition, Marcel Dekker, Inc., NY, 1979, pp. 106-120.
The basis of the prior art processes involves dissolving or dispersing the core material in a solution of the wall-forming material dissolved in a volatile, water-immiscible organic solvent. The organic phase is emulsified with an aqueous solution containing a surface active agent to form a dispersion of oil droplets which would yield microspheres upon removal of the organic solvent by evaporation (distillation or spray-drying), solvent extraction or freeze-drying. However, the products from these processes are agglomerated microspheres and not discrete particles, suitable for example, in parenteral applications.
U.S. Pat. No. 3,660,304 discloses a method for producing oily liquid-containing microcapsules using a mixture of high and low boiling point solvents, in an oil-in-water emulsion system.
U.S. Pat. No. 3,972,023 discloses a method for producing microcapsules by solvent evaporation from an oil-in-water emulsion, followed by chemical curing to harden the resultant microcapsules. The wall-forming polymer contains crosslinkable reactive groups.
Solvent removal from an emulsion is disclosed in U.S. Pat. No. 3,523,906 and U.S. Pat. No. 3,523,907 wherein an aqueous solution as core material was encapsulated by the emulsion method using a hydrophilic colloid such as gelatin or polyvinyl alcohol as the emulsifier.
The use of the emulsion process for microencapsulation of medicaments is described in U.S. Pat. No. 3,960,757 wherein a hydrophilic colloid (e.g., gelatin, polyvinyl alcohol) and/or a surface active agent (anionic or nonionic type having an HLB of not less than 10) is used as the emulsifier.
A mixed gelatin-nonionic surface active agent system in a similar process for preparing beads of biodegradable polymer e.g., polylactic acid containing progesterone was used by S. Yolles et al. in "Controlled Release Polymeric Formulations," edited by D. R. Paul and F. W. Harris, American Chemical Society, Washington, D.C., 1976, pp. 124-125. The microspheres formed were 250-420 micron diameter with some agglomerates present.
A process using an anionic surfactant, sodium dodecyl sulfate, in the emulsion process to encapsulate pesticides with polylactic acid is described in U.S. Pat. No. 4,272,398. The product was a coarse powder of large aggregates of microspheres, most of which were 177-595 microns.
Polyvinyl alcohol was employed as the emulsifier in a solvent evaporation process for obtaining microspheres of polylactic acid by L. R. Beck et al., "A New Long-Acting Injectable Microcapsule System for the Admiministration of Progesterone," Fertility and Sterility 31:5, 545-551 (1979). The microspheres were 10-250 microns and were free of agglomerates.
Using biodegradable polymers such as polylactic acid as the wall-forming material in microspheres for injectable application eliminates the need for surgical removal of the microspheres after delivery of the drug. For controlled release of drug suitable for parenteral administration, the microspheres should be free of agglomerates and the size should be large enough to provide adequate duration of release yet small enough not to restrict passage through the standard syringe needles. Thus, the maximum size would be about 150 microns for a conventional No. 20 gauge needle.
Although one of the major objectives of microencapsulation is to control the release rate of a core material, the prior art generally does not disclose a method for modifying a release rate.